Protein misfolding and aberrant polymerization have been implicated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion diseases. Sporadic forms of these protein conformational disorders are often much more prevalent than inherited forms of the diseases. Understanding how the sporadic disease is initiated may require elucidating other genetic and environmental factors that contribute to protein aggregation. The research proposed in this pilot project will address the causal relationship between one additional factor, the ubiquitin-proteasome system, and protein aggregation. The causal relationship between proteasomal activity, protein aggregation, and disease has been difficult to discern partially due to the concurrent appearance of cellular toxicity. We have employed the well-characterized prion protein aggregates in yeast as a model for further investigation of protein aggregates that can be toxic or non-toxic in cells. We have found that expression of a mutant form of ubiquitin associated with Alzheimer's disease enhances the toxicity of prion protein aggregates. The model system used in this proposal provides novel strategies for rapid screening of factors that modulate the cellular response to proteasomal impairment and toxic protein aggregates. In this pilot study we will identify cellular alterations that alleviate the effects of mutant ubiquitin expression. Future directions of this research may lead to new therapeutic avenues for Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Proteins need to be properly folded in a particular three dimensional structure for full functionality. The inability of proteins to maintain proper folding is the cause of several devastating human diseases. We are investigating how changes in the protein homeostasis, specifically in the protein degradation machinery, impact protein misfolding and aggregation. We are using a novel genetic system in order to determine how these problems can be corrected in the cell. [unreadable] [unreadable]